The present invention is directed to antibacterial compounds which are diastereomeric 5R,6S-6-(1R -hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids, viz., the 2-(1S-oxo-3R-thiolanylthio) variant of the formula (I) below, and the 2-(1R-oxo-3S-thiolanylthio) variant of the formula (II) below; the pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof; and intermediates and processes useful in the preparation of said diastereoisomers.
Antibacterial 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxyl ic acid, which is a diastereomeric mixture of two compounds, was earlier disclosed as a valuable antibacterial substance by Hamanaka, U.S. Pat. No. 4,619,924 and European patent application 130,025. Although detectable by analytical methods, the pure diastereomeric compounds of assigned structure have heretofore been unavailable. Disclosure of an improved process for that diastereomeric mixture from racemic cis-3-(acetylthio)thiolane 1-oxide, which employs mixed diastereomeric intermediates otherwise analogous to those presently used, will be found in a European patent application by Volkmann et al., scheduled for publication on May 27, 1987 under the No. 223,397.
Concerning the present optically active precursors, Brown et al., J. Am. Chem. Soc., vol. 108, pp. 2049-2054 (1986) have reported the synthesis of (S)-3-hydroxythiolane [inadvertently depicted as the (R)-isomer, but actually of configuration opposite to that of the present (R)-3-hydroxythiolane, of the formula (XI) below] by asymmetric hydroboration of 2,3-dihydrothiophene. Partial enzymic oxidation of racemic 3-hydroxythiolane by Jones et al., Can. J. Chem., vol. 59, pp. 1574-1579 (1981) permitted recovery of 3-hydroxythiolane containing the (R)-isomer in slight excess. Present optically active precursors (R)-(2-methanesulfonyloxyethyl)oxirane [of the formula (XIII) below wherein R.sup.9 =CH.sub.3 ] and (S)-2-bromo-1,4-di(methanesulfonyloxy)butane [of the formula (Xa) below wherein R.sup.8 =CH.sub.3 ] are known compounds; both preparable according to Shibata et al., Heterocycles, vol. 24, pp. 1331-1346 (1986); the former also according to Boger et al., J. Org. Chem., vol. 46, pp. 1208-1210 (1981).